Trial Information

Phase I Trial of Aflibercept (VEGF-Trap) With Radiation Therapy and Concomitant and Adjuvant Temozolomide in Patients With Malignant Glioma

PRIMARY OBJECTIVES:

I. To define the maximum tolerated dose (MTD) of aflibercept (VEGF Trap) with radiotherapy
(RT) and concurrent temozolomide (TMZ) when administered in patients with newly-diagnosed
glioblastoma (GBM) or gliosarcoma.

II. To define the MTD of aflibercept with adjuvant TMZ administered at 150mg/m2once daily
for 5 days every 28 days in patients with stable or recurrent malignant glioma (MG) after
RT.

III. To define the MTD of aflibercept with adjuvant TMZ administered at 100 mg/m2 once daily
for 21 days every 28 days in patients with stable or recurrent MG after RT.

IV. To characterize the safety profile of aflibercept in combination with RT and concomitant
TMZ in patients with newly-diagnosed GBM.

V. To characterize the safety profile of aflibercept in combination with adjuvant TMZ in
patients with stable or recurrent MG after RT.

SECONDARY OBJECTIVE:

I. To characterize the pharmacokinetic profiles of free and bound aflibercept and TMZ in
these patients

OUTLINE: This is a multicenter, dose-escalation study of aflibercept. Patients are assigned
to 1 of 3 treatment groups according to prior treatment and diagnosis.

Group 1 (newly diagnosed glioblastoma multiforme or gliosarcoma): Patients undergo involved
field partial brain radiotherapy (RT) once daily, 5 days a week (total of 30 fractions) and
receive concurrent oral temozolomide (TMZ) once daily for 6 weeks. Beginning 2 weeks after
the initiation of RT patients also receive aflibercept IV over 1 hour on days 1 and 15 and
continue until the end of RT. Beginning 4 weeks after completion of radiotherapy, patients
receive adjuvant oral TMZ once daily on days 1-5. Treatment with adjuvant TMZ repeats every
28 days for up to 12 courses.

Group 2 (stable or recurrent malignant glioma): Patients undergo radiotherapy as in group 1.
Patients receive oral TMZ on days 1-5. Treatment repeats every 28 days for up to 12*
courses. Patients also receive aflibercept IV over 1 hour on days 1 and 15 beginning on the
first day of TMZ treatment.

Group 3 (stable or recurrent malignant glioma): Patients undergo radiotherapy as in group 1.
Patients receive oral TMZ on days 1-5. Treatment repeats every 21 days for up to 12*
courses. Patients also receive aflibercept IV over 1 hour on days 1 and 15 beginning on the
first day of TMZ treatment.

In all groups, treatment continues in the absence of disease progression or unacceptable
toxicity.

Blood samples are collected periodically for analysis of pharmacokinetics by ELISA. Tumor
biomarkers and plasma angiogenic peptides are analyzed for correlation with response, and
tumor MGMT promoter methylation status is determined using methylation-specific PCR.

After completion of study treatment, patients are followed every 3 months.

Inclusion Criteria

Criteria:

- Creatinine < = 1.5 mg/dL or creatinine clearance = > 60 mL/min

- At least 28 days since prior major surgery or open biopsy

- INR < = 1.5

- Not pregnant or nursing

- Negative pregnancy test

- Karnofsky performance status 60-100%

- SGOT and SGPT < 2 times upper limit of normal (ULN)

- Bilirubin < 2 times ULN

- Life expectancy = > 12 weeks

- WBC = > 3,000/μL

- ANC= > 1,500/mm³

- Platelet count = > 100,000/mm³

- Hemoglobin = > 10 g/dL (transfusion allowed)

- At least 21 days since prior radiotherapy (groups 2 and 3)

- No prior Gliadel® wafers

- No concurrent major surgery

- Fertile patients must use effective contraception prior to, during, and for at least
6 months after completion of study treatment

- At least 28 days since prior significant traumatic injury No evidence of bleeding
diathesis or coagulopathy

- No serious or nonhealing wound, ulcer, or bone fracture

- No history of other cancer (except nonmelanoma skin cancer or carcinoma in situ of
the cervix), unless in complete remission and off of all therapy for that disease for
a minimum of 3 years

- No history of abdominal fistula, gastrointestinal perforation, intra-abdominal
abscess gastrointestinal bleeding or diverticulitis within the past 6 months

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